A number of justifications exist for formulating two or more antibiotics into a combined formulation, including targeting bacterial infections having more than one organism or type of organism where each requires a different antibiotic to treat the infection. Additionally, drug-resistant bacteria greatly increase the amount of antibiotic required for therapeutic treatment. Combinations of antibiotics with synergistic effects would reduce the overall amount of drug required and increase the effectiveness of the treatment.
Several combinations of antibiotics are in common use and certain combinations are specifically formulated to be inhaled to treat infections of the respiratory tract including the lungs. Because lung infections are notoriously difficult to treat with oral or intravenous administration of antibiotics, combinations of inhaled antibiotics are particularly valuable. Also, where a lung infection is a combination of Gram-negative and Gram-positive bacteria, antibiotics against each are necessary. Aerosol antibiotic therapy to treat Gram-negative pneumonia in patients on mechanical ventilation has been studied for over 30 years; however, to date no multicenter placebo controlled randomized trial has proven efficacy. There are multiple technical reasons for this, including drug delivery and choice of antibiotic. Additional unique challenges treating bacterial infections in patients on respirators and related solutions to those challenges are described in US 2013/0014759, which is incorporated herein by reference.
One example of an antibiotic combination would include fosfomycin. Fosfomycin is a broad-spectrum antimicrobial with activity against most of the aerobic Gram-positive and Gram-negative bacteria. Fosfomycin is a phosphonic acid derivative, which acts primarily by interfering with bacterial peptidoglycan synthesis, thereby disrupting bacterial cell wall synthesis. Fosfomycin does not undergo metabolism in the body and is primarily excreted unchanged in the urine by glomerular filtration.
Aminoglycosides are a group of bactericidal drugs sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. The group includes streptomycin, neomycin, kanamycin, amikacin, gentamycin, tobramycin, sisomicin, arbekacin, netilmicin, paromomycin, and spectinomycin. Aminoglycosides inhibit protein synthesis in bacteria by inhibiting the protein synthesis function of the bacterial ribosome. All aminoglycosides are potentially ototoxic (damage to the ear) and nephrotoxic (damage to the kidneys). Because of their toxicity and the availability of less toxic antibiotics, aminoglycosides have been used less often in recent years and to treat resistant Gram-negative organisms that are sensitive only to aminoglycosides. Combinations of tobramycin with fosfomycin are described in Baker et al. U.S. Pat. No. 7,943,118.
Amikacin is a synthetic aminoglycoside used to manage infections caused by Gram-negative bacilli resistant to gentamycin and tobramycin. Amikacin is most commonly used on serious Gram-negative infections involving skin and soft tissue, bone and joint, abdominal and urinary tract, and severe respiratory infections. Amikacin's use can include coverage against some aerobic Gram-positive bacteria, which include E. coli, klebsiella, proteus, pseudomonas, salmonella, enferobacter, serratia and mycoplasma. Like other aminoglycosides, amikacin has a similar potential for ototoxicity and nephrotoxicity especially when given by parenteral administration due to systemic absorption. Amikacin used for intravenous administration is formulated as amikacin-sulfate.
Both fosfomycin and amikacin have been used in the past as inhaled antibiotics. However, each of fosfomycin and amikacin has unique manufacturing and storage characteristics based on their unique chemistry and these characteristics significantly affect their usefulness when combined and used to treat infections in patients. The performance characteristic of each antibiotic, either alone or in combination, can be improved by formulation strategies that improve the storage and safety characteristics of each antibiotic agent. In some cases, common reaction characteristics exist across classes of antibiotics and formulation strategies can be extended from individual species to the broader class of antibiotic. Where formulated for inhalation, other aminoglycosides, such as tobramycin and gentamycin can also be improved by formulation strategies to improve storage and safety characteristics.
Accordingly, a need exists for compositions, manufacturing and storage methods, and systems for combining combinations of fosfomycin and aminoglycosides to maximize the utility of specific antibiotic combination formulations and to enhance their safety.